We will develop a cell-based assay that allows us to detect changes in the ability to process histone pre- mRNA. The reporter encodes a portion of a histone mRNA including the 3' end formation signal fused to a downstream GFP open reading frame followed by a polyadenylation signal. Failure to process at the histone 3' end will result in read-through to the polyadenylation site resulting in production of GFP. We have successfully carried out a genome-wide RNA interference screen using this approach. We will adapt the screen to screening for chemical compounds. Using an antisense oligonucleotide which blocks U7 snRNP, we have shown that we can readily detect the inhibition of histone pre-mRNA processing by fluorescence of the reporter. We are adapting the screen to an automated microscope which can rapidly read the 384 well plates.